Carisbamate（RWJ-333369）在大鼠齒回抑制突觸前麩胺酸釋放

Abstract

Carisbamate (RWJ-333369) is a novel neuromodulator and shows a broad spectrum antiepileptic activity. We suggest that this neuroprotection effect might act through the regulation of excitatory synaptic transmission on DG. Our research evaluated its effect on excitatory signal transmission to dentate gyrus (DG) granule cell in rat hippocampus slice by whole-cell patch clamp technique. Evoked AMPA/NMDA receptor-mediated excitatory postsynaptic currents (eEPSCAMPA/NMDA) were recorded by whole-cell patch-clamp recording from the granule cells of DG in brain slice preparation of young Wistar rats (60-120 g, P21). We also used paired-pulse stimulation, exogenous AMPA application and AMPA receptor-mediated miniature EPSC (mEPSCAMPA) recording to evaluate the effects of carisbamate. Our results showed that carisbamate inhibited eEPSCAMPA/NMDA in a concentration-dependent manner. The decrease of paired-pulse ratio in 100 mM at 50 and 100 ms interval suggests that carisbamate acts presynaptically to reduce AMPA-receptor mediated current from perforant pathway. The response to exogenous AMPA application and mEPSC recording in the presence of TTX also showed that carisbamate had no effect on AMPA receptor. Furthermore, L-type Ca2+ channel blocker didn’t mask the reduction of eEPSCAMPA by 100 mM carisbamate. DG plays an important role in epilepsy, especially in temporal lobe epilepsy (TLE). The ability to regulate hippocampus is attenuated in TLE, which makes the seizure threshold lower. The inhibition of presynaptic glutamate release by carisbamate may contribute to its antiepileptic action.